Hepatitis C is the commonest cause of chronic hepatitis in the US and can lead to progressive liver injury with the development of cirrhosis, liver failure and liver cancer. Liver injury may be caused by an interaction of the virus with the host immune response leading to inflammation and fibrosis in the liver. We plan to examine the mechanism of HCV induced liver injury in three distinct groups of patients: 1) those with chronic HCV infection and evidence of moderate to severe necroinflammatory disease, who are at average risk of progression to cirrhosis; 2) those with persisting viremia but normal or minimally elevated transaminases and normal or mildly inflamed liver biopsies, who are at low risk of progression to cirrhosis; and 3) patients with chronic HCV liver disease and active daily alcohol use (greater than 50 gm/day), who are at the highest risk of progression of liver disease. Specifically, we propose to evaluate the role of intrahepatic viral load on immune response and liver injury by measuring liver derived CTL response and cytokine production and correlating the immune response to the degree of liver injury. The response in the liver will be compared with that seen in the periphery to determine whether there is compartmentalization of immune responses and whether peripheral immune response can correlate with the injury and immune response seen in the liver. The role of anti-viral therapy and alcohol on these responses will also be studied. These studies may lead to insights on the mechanism of liver injury and help define those patients who are most likely to have progressive liver injury.